Stomatoxerosis is generally called "xerostomia" or "dry mouth" and its manifestation is characterized by decreased or deficient secretion of saliva caused by various factors. Since many factors are related to the secretion of saliva, it is very difficult to investigate the cause of xerostomia.
Considering the causes, it is known that various diseases which cause organic changes in salivary glands, lesions in salivary glands accompanied by systemic diseases, necrosis of salivary gland cells caused by radiotherapy, HIV infection, hypofunction of scretion caused by aging, the effect of various medicines and, further, mental fatigue or stress due to complex social life situations bring about these symptoms.
With age, stomatoxerosis is a common symptom, which is observed in 16% of males older than 70 years and 25% of females of the same age as above and are considered to be caused by a regressive change in salivary glands due to aging.
Further, there are many pharmaceutical drugs which cause hyposecretion of salivary glands, e.g., it has been reported that the number of such drugs is more than 100, and that the ratio of the patients complaining with dry mouth increased as the number of the species of drugs administered increased. For example, diuretics such as trichloromethiazide, furosemide, etc., antihypertensive such as reserpine, clonidine hydrochloride, etc., anticholines such as atropine sulfate, etc., antihistamines such as chlorpheniramine maleate, etc., various types of antitussives and expectorants, antiparkinsonism agents, psychotropic agents, antidepressants, tranquilizers, muscle relaxants, etc., are exemplified as drugs causing dry mouth.
In addition, while radiotherapy has been playing an important role for the treatment of malignant tumors in the field of stomatosurgery and otolaryngology, severe injury to salivary glands is inevitable due to a broad radiation area during the treatment, leading to severe xerostomia. The number of such patients as the above is anticipated to increase with the prevalence of radiotherapy.
Symptoms of xerostomia include not only intraoral dryness but also many and severe problems in daily life such as intraoral utrication, pain, glossalgia, dysgeusia, atrophy of papilla lingualis, inflammation of tunica mucosa oris, ulceration, rhagades of lingua orangulus oris, difficulties in mastication, somatic swallowing or conversation, etc.
Therefore, an appropriate countermeasure to the above is strongly required.
At present the methods of treatment of these symptoms include artificial saliva, mouth-wash, etc., but these have only a temporary wetting effect in the mouth. Alternatively, parotin, cepharanthin and various kinds of chinese medicines are used in practice, but have adverse effects or insufficient therapeutic effect. Thus, satisfactory therapeutic methods for xerostomia not caused by Sjogren's syndrome have not yet been established.
The object of the present invention is to synthesize chemical compounds to augment saliva secretion by stimulating exocrine glands, particularly, the muscarinic M.sub.3 receptor; to provide a therapeutic agent for the treatment of xerostomia without systemic adverse effects and with the least toxicity and to alleviate pain in patients with dry mouth, based on recent developments in research on parasympathetic nervous system, that is, cholinergic receptors.
The present inventors have synthesized various compounds and investigated their efficacy to attain the above objects and found that a certain kind of derivative of spirooxathiolane-quinuclidine, or an acid addition salt thereof having a formula [I] exhibits an excellent effect and accomplished the present invention.